Lymphangioleiomyomatosis (LAM) is a rare disease primarily found in females and is characterized by a diffuse interstitial infiltrate of atypical smooth muscle cell lesions in the lung parenchyma resulting in airway restriction. The etiology of the disease is unknown but is thought to involve hormonal regulation because it usually presents between menarche and menopause. Additionally, LAM is often found in patients with mutations in tuberous sclerosis complex (TSC), suggesting that inactivation of TSC can contribute to its development. We are studying uterine development and associated pathologies by conditionally deleting and/or activating candidate genes in pathways critical for normal differentiation and function. We have created mice with uterine-specific leiomyomas (fibroids) by either constitutively activating [unreadable]-catenin or by expressing a truncated allele of adenomatous polyposis coli (APC) and we have shown preliminary evidence that the leiomyomas develop as a result of vascular hemorrhaging and subsequent hypertrophic scarring. The Mullerian duct-derived internal female reproductive tract organs (uterus, oviduct, cervix, and cranial portion of the vagina) are the only structures from the bipotential mammalian embryo not found in males, suggesting that the hormonally responsive mesenchymal stromal cells of the uterus might be the source of the cells for pulmonary fibrosis and account for the female-specificity of LAM. We hypothesized that pulmonary LAM might be caused by uterine vascular pathologies that allow intravasation of uterine stromal cells that can subsequently lodge and proliferate in the lungs. Histological analysis of the lungs from our mouse models with uterine hemorrhaging and leiomyomas showed fibrotic lung plaques similar to that observed in human LAM that were also HMB45-, aSMA- and desmin-positive, markers for human LAM. We propose to investigate this hypothesis further with the following Specific Aims: (1) confirm that cells in the lung lesions are derived from the uterus, (2) determine whether uterine mesenchymal cells can be detected in peripheral blood, (3) test the hormone responsiveness of the smooth muscle cells in the lung lesions, and (4) assess the marker profile of lung lesions for comparison with human LAM. The results from these studies will lay the foundation for continued investigation of the triggers and signaling pathways involved in the development of the LAM lesions as well as provide an in vivo model system for preclinical studies of therapeutics targeting those pathways. PUBLIC HEALTH RELEVANCE: One of the major unknowns in lymphangioleiomyomatosis (LAM) research is the cell or tissue of origin for the smooth muscle cells that infiltrate the lung to form the fibrotic lesions. We have generated mice with defective wound healing in uteri, which results in hemorrhaging, hypertrophic scarring and fibroids. Our preliminary results investigating the lungs suggest that circulating post-traumatic uterine cells might be the cells that cause LAM. The proposed studies will investigate whether the uterine cells are the source of fibrotic cells found in LAM, whether the LAM lung lesions are hormonally responsive, and whether these mutant mice will be a needed model system for investing the mechanisms and pathways involved in the infiltration of the lungs with fibrotic cells and for preclinical studies of possible therapeutic intervention.